DESCRIPTION (as provided by applicant): The lack of effective vaccines and therapeutic treatments for many viruses presents a significant health concern. Host defenses against viruses require adaptive immune functions provided by both B cells and T cells, but the cellular and molecular processes that control the functions and cell fate decisions of these cells are incompletely understood. Although the persistence of viral antigens, the cytokine milieu in local microenvironments, the concentration and placement of immune cells in lymphoid and non-lymphoid organs, and the availability and type of co-stimulation can all dramatically affect the ultimate biological outcome of an immune response to virus infection or vaccination, it is unclear how these factors are controlled or how viruses manipulate each of these factors to evade or subvert immunity. These basic knowledge gaps limit our ability to rationally design new vaccines and develop interventions to treat virus-mediated diseases. Therefore the overall goal of this U19 Program is to determine how various types of virus infections (chronic-systemic, acute-systemic, and acute-mucosal) affect the factors described above and lead to specific types of immune responses that may be beneficial or pathologic. In order to meet this goal, five labs with complementary expertise in human and mouse antiviral immunology will work collaboratively to address some of these key unresolved issues in antiviral immunity. In Project 1, Troy Randall at UAB will determine how Tfh responses are controlled by IL-2 signaling and availability. In Project 2, Allan Zajac at UAB will determine how antiviral CD8+ T cells responses are controlled by adhesion molecules and T cell clustering. In Project 3, Frances Lund at UAB will determine how antiviral B cell responses are controlled by IFN? signaling and availability. In Project 4, Nicole Baumgarth of UC Davis will determine how natural and induced antiviral IgM responses are controlled. These projects will be facilitated by Core A - Administration and Biostatistics (Troy Randall), Core B - Viral Stocks and Reagents (Frances Lund), and Core C - Human Immunology (Frances Eun-Hyung Lee, Emory). Importantly, all projects will be able to examine virus-specific B and T cells using tetramer reagents developed by Core B. In addition, although many of the mechanistic studies in each project will be performed using mouse models, the projects will also test key hypotheses in humans via interactions with the Human Immunology Core (Core C).